Vitamin A and its derivatives (retinoids) have profound effects on human skin As well as playing a role in the control of development, retinoids effect growth differentiation and malignant transformation of both epithelial and mesenchymal cells. Recent data has also suggested a role for retinoids in the reversal of age associated changes in human skin. In order for retinoids to have an effect on a cell the presence of a high affinity receptor specific for vitamin A is required. Three genes for distinct retinoic acid receptors have recently been cloned and the: all members of a large multi-gene family of nuclear receptors which act as ligand inducible transcriptional enhancer factors. We propose a series of studies of skin-derived fibroblasts in neonatal, young and old humans aimed at characterizing the response of these cells, at the genetic levy to retinoids and changes that occur in the expression of the genes as a function of donor age. Since the regulation of expression of the RAR genes has never been explored in any skin-derived cell, whether mesenchymal (fibroblasts or epithelial (keratinocytes), we will begin our studies using neonatal fibroblasts. In this way we will establish, at the level pf mRNA accumulation and transcription, the effect of specific ligands on FAR gene expression. Finally, we propose to examine the effect of aging, using an in vivo human model, on RAR gene expression. We hope to identify age-related defects in tissue specific RAR gene expression, which are Potentially reversible, that might contribute to the multitude of structural and functional abnormalities evident in aged skin. GRANTS=U01AA08798 The goal of this project is to implement and evaluate an intensive, long-term case management program for a group of homeless chronic public inebriates who represent the most frequent users of the King County Detoxification Center. Ten case managers will be hired, each of whom will have a case load of about 15 clients. Subjects will be 120 Native American men, 120 mixed race (white, black, Hispanic and Asian) men, and 60 women. Within each subgroup, subjects will be randomly assigned to equal sized experimental (longterm intensive case management) and control (treatment as usual) conditions. All subjects will be interviewed, and have blood samples drawn for liver function tests, at admission and at 6 month follow-up periods for two years. Data will be analyzed to determine (a) whether intensive case management improves the clients' pattern of social service utilization, (b) whether intensive case management improves the clients' quality of life, (c) how the costs and cost-effectiveness of case management compares with treatment as usual, and (d) whether specific client or case manager characteristics are associated with successful outcome. Based on pilot study experience, we expect that case management will reduce alcohol consumption, reduce detoxification admissions, increase treatment service utilization, improve financial and residential stability, and improve family relations.